A NEW STRATEGY TO DECREASE NMDA RECEPTOR CO-ACTIVATION VIA SERINE RACEMASE INHIBITION - The long goal of this research is to develop and commercialize a serine racemase inhibitor for neurological disease. In phase I we propose to explore the therapeutic utility of serine racemase inhibition in cell culture and animal models of neurological disease. D-serine, the enantiomer of L-serine, comprises about one third of the total serine concentration in the brain. Emerging evidence suggests that D-serine acts as a coagonist of the NMDA receptor. Serine racemase was recently identified in mammalian brain and suggested to be the source of endogenous D-serine. Enzymatic inhibition of serine racemase would lower D-serine levels, reduce NMDA receptor activation, and provide a novel approach of modulating receptor activity. NMDA receptor overactivation has been associated with several CNS disorders including stroke and chronic pain. Through both random and selective screening of commercially available and Guilford's chemical libraries, we have identified three structurally distinct compounds that inhibit serine racemase activity with IC50 values of 2- 30 micromolar. To our knowledge, these represent the most potent serine racemase inhibitors identified to date. The first aim of our proposed studies is to find analogs of these three inhibitors with improved potency and at least 10-fold selectivity for serine racemase. Second, we will evaluate these inhibitors for their ability to attenuate D-serine synthesis and protect against NMDA-induced neurotoxicity in rat primary cortical cultures. Finally, we will evaluate selected inhibitors for their ability to attenuate D-serine synthesis and protect against neuronal injury following middle cerebral artery occlusion in a rat model of stroke.